title: Role of IGF-1 pathway in lung fibroblast activation.
abstract: BACKGROUND
  IGF-1 is elevated in pulmonary fibrosis and acute lung injury, where fibroblast activation is a prominent feature. We previously demonstrated that blockade of IGF pathway in murine model of lung fibrosis improved outcome and decreased fibrosis. We now expand that study to examine effects of IGF pathway on lung fibroblast behaviors that could contribute to fibrosis.
  
  
  METHODS
  We first examined mice that express αSMA promoter upstream of GFP reporter treated with A12, a blocking antibody to IGF-1 receptor, after bleomycin induced lung injury. We then examined the effect of IGF-1 alone, or in combination with the pro-fibrotic cytokine TGFβ on expression of markers of myofibroblast activation in vitro, including αSMA, collagen α1, type 1, collagen α1, type III, and TGFβ expression.
  
  
  RESULTS
  After bleomycin injury, we found decreased number of αSMA-GFP + cells in A12 treated mice, validated by αSMA immunofluorescent staining. We found that IGF-1, alone or in combination with TGF-β, did not affect αSMA RNA expression, promoter activity, or protein levels when fibroblasts were cultured on stiff substrate. IGF-1 stimulated Col1a1 and Col3a1 expression on stiff substrate. In contrast, IGF-1 treatment on soft substrate resulted in upregulation of αSMA gene and protein expression, as well as Col1a1 and Col3a1 transcripts. In conclusion, IGF-1 stimulates differentiation of fibroblasts into a myofibroblast phenotype in a soft matrix environment and has a modest effect on αSMA stress fiber organization in mouse lung fibroblasts.
authors.affiliation: Center for Lung Biology, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, 850 Republican St, Box358052, Seattle 98109, WA, USA. lschnapp@uw.edu.
authors.forename: Chi F
authors.initials: CF
authors.lastname: Hung
authors.forename: Maryam G
authors.initials: MG
authors.lastname: Rohani
authors.forename: Sung-Soon
authors.initials: SS
authors.lastname: Lee
authors.forename: Peter
authors.initials: P
authors.lastname: Chen
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Schnapp
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001761:Bleomycin / Q000009:adverse effects; D002454:Cell Differentiation / Q000187:drug effects*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D066298:In Vitro Techniques; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology*; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000187:drug effects* / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000187:drug effects; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000199:Actins; D000911:Antibodies, Monoclonal; D016212:Transforming Growth Factor beta; D001761:Bleomycin; D007334:Insulin-Like Growth Factor I; D003094:Collagen; D017526:Receptor, IGF Type 1